The addictive nature of methamphetamine (METH) is due, at least in part, to drastically increased extracellular dopamine. Though no current therapeutic for METH addiction is available, numerous compounds have been investigated for efficacy in METH addiction recovery. The difficulty in therapeutic development is finding a molecular target that both modulates dopamine release and is preferentially expressed within dopamine neurons to limit adverse effects of treatment. Expression of the synaptic glycoprotein 2C (SV2C) is largely restricted to areas rich in dopaminergic innervation, such as the midbrain and striatum. Additionally, preliminary experiments conducted by the applicant demonstrate the importance of SV2C in normal dopamine release and storage. Genetic ablation of SV2C results in a 50% reduction of vesicular release in striatal brain slices, as measured by fast scan cyclic voltammetry, and a 20% reduction in vesicular storage capacity, as measured by radioactive dopamine uptake. The restricted localization of SV2C coupled with the important role it plays in dopamine neurotransmission identify it as a prime candidate for potential therapeutic development. The purpose of this proposal is to delineate the effect of genetic deletion of SV2C on the neurochemical and behavioral changes associated with METH administration in mice. This project is both timely and highly translational, as compounds that selectively bind SV2C have been created (UCB Pharma), though they have not been investigated for modulation of dopamine signaling.
Methamphetamine (METH) abuse is a significant public health concern, with annual statistics documenting over 100,000 new METH users and an estimated societal cost of over $24 billion in the United States. Drug addiction treatment strategies ideally involve cognitive-social therapy coupled with pharmacological treatment (such as methadone for heroin addiction). As there are currently no pharmacotherapeutics available for the treatment of METH addiction, this project identifies a novel mediator of dopamine neurotransmission that may provide a novel target for drug development.
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| Lohr, Kelly M; Chen, Merry; Hoffman, Carlie A et al. (2016) Vesicular Monoamine Transporter 2 (VMAT2) Level Regulates MPTP Vulnerability and Clearance of Excess Dopamine in Mouse Striatal Terminals. Toxicol Sci 153:79-88 |
| Stout, Kristen A; Dunn, Amy R; Lohr, Kelly M et al. (2016) Selective Enhancement of Dopamine Release in the Ventral Pallidum of Methamphetamine-Sensitized Mice. ACS Chem Neurosci 7:1364-1373 |
| Lohr, Kelly M; Stout, Kristen A; Dunn, Amy R et al. (2015) Increased Vesicular Monoamine Transporter 2 (VMAT2; Slc18a2) Protects against Methamphetamine Toxicity. ACS Chem Neurosci 6:790-9 |
